Repetitive mild closed head injury (rCHI) is a common form of mild traumatic brain injury (mTBI) among military personnel in both combat and non-combat missions. rCHI can result in sustained cognitive decline and neurobehavioral changes (such as anxiety and depression-like behaviors) [1]. More recently rCHI has also been linked to the formation of a neurodegenerative condition called chronic traumatic encephalopathy (CTE). CTE is pathologically characterized by protein aggregate deposit found in the cortex and other brain regions, post-mortem. Two major proteins found in these CTE protein deposits are microtubule-associated protein Tau and TAR DNA-binding protein (TDP-43) [2-5]. Patients with CTE may show symptoms of dementia, such as memory loss, confusion, anxiety, depression and aggression, which generally appear years or decade(s) after the occurrence of neurotrauma. The Central Hypothesis to be tested is that chronic cognitive and neurobehavioral changes following repetitive mTBI (rCHI) is closely linked to post-injury Tau and TDP-43 proteinopathy development. In addition, the proposed work will not only allow us to test this hypothesis, but also enable us to validate novel CTE biomarkers tests as well as to examine a novel Tau, TDP-43 proteinopathy-based immunotherapy strategy towards improvement of chronic neurobehavioral deficits. Three specific aims are proposed in this application to address the central hypothesis. In Specific Aim 1, we will subject wildtype mice to repetitive close head injury (rCHI) and follow them from subacute to chronic period (up to 18 mo.) to characterize cognitive and neurobehavioral changes, overall neuropathology and their correlation with time-dependent CTE-like Tau/P-tau and TDP-43 protein accumulation /proteinopathy signatures in brain tissue and biofluid. In Specific Aim 2 we will subject human-tau (hTau) transgenic mice and TDP-43 overexpressing transgenic mice to rCHI and follow them from subacute to chronic period to examine if they develop worsened cognitive and neurobehavioral changes, neuropathology and accelerated, exaggerated Tau/TDP-43 proteinopathy signatures in brain tissue and biofluid. Lastly, in Specific Aim 3, we will combine our learning from rCHI models in Aim 1 & 2 to test potential effects of Tau/P-Tau and TDP-43 immunization as novel immunotherapy for reducing rCHI-induced Tau and TDP-43 proteinopathy load and mitigating chronic cognitive, neurobehavioral and neuropathological changes in wildtype, hTau, TDP-43 transgenic and/or hTau/TDP-43 double transgenic mouse lines. This proposed systemic study will advance our understanding of the neurobehavioral (anxiety, depression, cognitive dysfunctions) and their potential linkage to the biochemical/protein changes of aggregation-prone proteins such as Tau and TDP-43 (proteinopathy) and CTE- like neurodegenerative cascade during the chronic phase of TBI. Such knowledge can translate into the ability for VA to devise better management tools and improved Veteran patient care. Our findings will also help us better diagnose chronic TBI including ultrasensitive biofluid-based Tau/P-tau and TDP-43-biomarker tests. Furthermore our research also points to a novel and promising immunotherapeutic strategy to treat such conditions. Taken together, these are all significant biomedical advances consistent with the research mission of the NF/SG VHS and VA and meet the full intent of the RFA. Importantly, the learning from this rodent studies and the immunotherapy approach can rapidly translate into clinical studies with Veterans who are at risk of developing post-TBI CTE.